1. Field of the Invention
The present invention relates to novel enkephalin analogs, salts and hydrates thereof, as well as a therapeutic composition containing at least one of the enkaphalin analogs.
2. Related Arts
Opiate alkaloids such as morphine induce a strong analgesic effect, but they also cause physical and psychological dependence and addiction as side effects.
Early in 1970, it was confirmed that opiate receptors are localized in mammalian brain; since then, numerous studies have been done to discover endogenous morphine-like substances which can not cause physical and psychological dependence and addiction. Hughes et al. have isolated two pentapeptides as endogenous opioid peptides [Hughes et al., "Nature" 258, 577 (1975)]. Enkephalins produce a weak and short-lived analgesia following intracerebroventricular (i.c.v.) or intravenous (i.v.) administration to mice and rats. .beta. -Endorphin, which consists of 31 amino acid residues and is a fragment of .beta. -lipotropin, has marked and long-lived analgesic activity following i.c.v. or i.v. administration. However, it is very difficult to massproduce .beta. -endorphin, because it is a high molecular weight polypeptide. Therefore, .beta. -endorphin has not been employed for an analgesic drug.
Shimohigashi et al. have reviewed the studies on synthetic enkephalins [Shimohigashi et al. "Protein, Nucleic acid, Enzyme" 28, 1321 (1983)]. The molecular structure of synthetic enkephalins has been designed to yield enkephalins with the following characteristics: a) lower molecular weight compounds which can be easily prepared, b) higher affinity for the receptors, c) resistance to degradation by enzymes such as aminopeptidase, carboxypeptidase, enkephalinase, and the like, d) easy absorption and diffusion in vivo, e) ability to pass through the blood-brain barrier, f) administration in oral dosage form, g) minimal side effects, and so on. For the chemical modifications in Met- and Leu-enkephalins each amino acid residue in the sequence has been replaced by others or chemically modified, or the enkephalin has been shortened or cyclized; however, no enkephalin analogs have been applied to patients as the analgesic drugs.
In 1980, Rodbard et al. reported symmetrical dimers of enkephalin analogs of the following formula as new synthetic enkephalins (U.S. Pat. No. 4,468,383). ##STR2## or an alkylene group having from 1 to 22 carbon atoms or a direct bond, and ##STR3##
The compounds in which R is H-Tyr-D-Ala-Gly and X is C.sub.1 -C.sub.22 -alkylene show more selectivity for .mu. than for to .delta. -receptors, particularly, DTRE.sub.2 in which X is C.sub.2 -alkylene, shows about 400-fold greater selectivity for .mu. than for .delta. in receptor binding assay [Lutz et al., "Eur. J. Pharmacol." 111, 257 (1985)]. When this compound was assayed using bioassays for opiate activity (GPI and MVD assays), it showed morphine-like activities and greater selectivity for .mu. than for .delta. [Shimohigashi et al., "Peptide Chemistry 1985" p. 51 (1986)].